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Routine preoperative lymphoscintigraphy is not necessary prior to sentinel node biopsy for breast cancer
SCIENTIFIC PAPERS
Routine Preoperative Lymphoscintigraphy Is Not Necessary Prior to Sentinel Node Biopsy for Breast Cancer William E. Burak, Jr., MD, Michael J. Walker, MD, Lisa D. Yee, MD, Julian A. Kim, MD, Sanjoy Saha, MD, George Hinkle, RPh, John O. Olsen, MD, Rodney Pozderac, MD, William B. Farrar, MD, Columbus, Ohio
BACKGROUND: This prospective study was performed to ascertain the added benefit of lymphoscintigraphy to a standard method of intraoperative lymphatic mapping and sentinel node biopsy for breast cancer. METHODS: Patients with invasive breast cancer were injected with 99mTc sulfur colloid prior to sentinel node biopsy; preoperative lymphoscintigraphy was then performed in half of the patient population. RESULTS: Sentinel node identification was possible in 45 of 50 patients (90%). All 14 patients (31%) with axillary nodal metastases had at least one histologically positive sentinel node (0% false negative rate). Lymphoscintigraphy revealed sentinel nodes in 17 of the 24 patients (70.8%) imaged. All 17 of these patients had one or more axillary sentinel nodes identified using intraoperative lymphatic mapping. In addition, 5 of 7 patients with a negative preoperative lymphoscintogram had an axillary sentinel lymph node(s) identified intraoperatively. None of the tumors showed drainage to the internal mammary lymph node chain by lymphoscintigraphy despite the fact that there were 5 patients with inner quadrant tumors. There was no significant advantage with respect to sentinel lymph node localization (91.7% versus 88.5%, P ⴝ not significant) or false negative rate (0%, both groups, P ⴝ not significant) in the group undergoing preoperative lymphoscintigraphy when compared with the patients in whom lymphoscintigraphy was not performed. CONCLUSIONS: Preoperative lymphoscintigraphy adds little additional information to intraoperative lymphatic mapping, and its routine use is not
From the Division of Surgical Oncology, (WEB, MJW, LDY, JAK, SS, WBF), Department of Surgery, and the Division of Nuclear Medicine, (GH, JOO, RP), Department of Radiology, Arthur G. James Cancer Hospital and Research Institute, Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Requests for reprints should be addressed to William E. Burak, Jr., MD, N914 Doan Hall, 410 W. 10th Avenue, Columbus, Ohio 43210. Manuscript submitted October 16, 1998, and accepted in revised form March 8, 1999.
© 1999 by Excerpta Medica, Inc. All rights reserved.
justified. Am J Surg. 1999;177:445– 449. © 1999 by Excerpta Medica, Inc.
I
ntraoperative lymphatic mapping and sentinel lymph node biopsy is currently undergoing evaluation as an alternative to axillary lymphadenectomy in the clinically node-negative breast cancer patient. Several reports have described the initial success of this minimally invasive alternative to routine lymph node dissection in selected patients.1– 6 Localization of a sentinel node has been shown to be feasible in more than 90% of patients, with falsenegative rates generally less than 10% in larger series of patients. The various techniques utilized involve the use of blue dye and/or radiolabeled colloid as lymphatic mapping agents. Preoperative lymphoscintigraphy is very useful in determining draining nodal basins prior to sentinel node biopsy in patients with melanoma because multiple basins will sometimes drain the same lesion and in transit nodes or unusual locations of sentinel nodes can be recognized prior to surgery.7 Unlike melanoma, breast cancer lymphatic drainage patterns are fairly predictable, with the vast majority of lesions exhibiting primary drainage to axillary lymph nodes. Nevertheless, nonaxillary sentinel nodes have been demonstrated in up to 10% of patients using an intraoperative gamma detector probe.6 To date, the role of preoperative lymphoscintigraphy in breast cancer patients has not been determined,8 although it has been utilized in several major studies as an aid in sentinel node identification.5,9 This prospective study aimed to ascertain the impact of preoperative lymphoscintigraphy on the success and accuracy of intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer.
METHODS Patient Selection Fifty patients were enrolled in this nonrandomized prospective study after signing informed consent approved by the Ohio State University Human Subjects Committee. Patients who had a histologic or cytologic diagnosis of breast carcinoma and were to undergo axillary dissection were considered for enrollment if they had unifocal disease, were nonpregnant, and had no palpable axillary adenopathy. Patients with a history of inflammatory breast carcinoma or neoadjuvant therapy were considered ineligible. The first 24 patients underwent preoperative lymphoscintigraphy followed by sentinel node biopsy, while the remaining 26 patients underwent sentinel node biopsy without a preoperative lymphoscintigraphy study. 0002-9610/99/$–see front matter PII S0002-9610(99)00088-4
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Preoperative Lymphoscintigraphy Filtered (0.22 micron) technetium-99m sulfur colloid was injected into the breast parenchyma in a four-quadrant technique around the palpable tumor or biopsy cavity. Each of the four injections was composed of 1 mL saline containing 100 Ci of radiolabeled colloid. For patients who had undergone either a stereotactic or ultrasoundguided core needle biopsy, a single injection of 400 Ci of radiolabeled colloid in 4 mL saline was administered under mammographic or ultrasound guidance at the same time as the needle-wire localization procedure. Preoperative lymphoscintigraphy was performed 30 minutes and at least 2 hours following injection using biplanar imaging. During the first 30 minutes, a 20-minute cine of the chest (anterior projection) was obtained followed by intermittent static images. The framing rate for the cine was 30 seconds per frame, and scintillation camera parameters were 20% window about the 140 keV photopeak. Static images were for 5 minutes’ duration each. The injection site was shielded with lead to enhance visualization of an axillary or mediastinal node. With visualization of the sentinel node(s), additional images in varying degrees of obliquity were performed for more accurate localization of the node(s). When the node was localized, the overlying skin was marked with indelible ink to help facilitate intraoperative node detection. Patients were then transferred immediately to surgery. Intraoperative Lymphatic Mapping Intraoperative lymphatic mapping (ILM) was performed using a combination of blue dye and a hand-held gamma detector probe (Neoprobe Corporation, Dublin, Ohio) to identify radioactivity from lymph nodes containing radiolabeled colloid. Approximately 4 to 5 mL of isosulfan blue dye (Lymphazurin 1%; Ben Venue Laboratories, Bedford, Ohio) was injected into the breast parenchyma in the same fashion as the radiolabeled colloid using either a fourquadrant technique (1 mL per injection) or through the previously placed localization needle. Routine transcutaneous probing of the axillary, internal mammary, and supraclavicular basins was performed. The gamma detector probe displayed counts per second in the scanning mode. “Hot spots” were defined as islands of radioactivity where counts decreased when the probe was moved in any direction from this point. Five to ten minutes following blue dye injection, an axillary incision was made, and attempts were made to identify a blue or radioactive node using visual inspection and the hand-held gamma detector probe. Nodes that demonstrated the presence of blue dye (or had a blue afferent lymphatic) and/or had the presence of radioactive counts above the surrounding tissues were removed and sent to pathology separately. The excised node was probed and counts were obtained to compare with counts of excised adjacent fat to assure the node had counts at least twice that of surrounding fat. A level I/II axillary node dissection was then carried out. The axillary contents were then probed to identify any additional radioactive nodes. Lymph nodes were evaluated using standard hematoxylin and eosin staining. Fisher’s exact test and the Mann-Whitney U test were used in the statistical analysis. 446
TABLE I Characteristics of Sentinel Nodes Sentinel Node* Blue only Radioactive only Blue and radioactive Total
Number 5 (7.7%) 19 (29.2%) 41 (63.1%) 65 (100%)
* Nodes identified intraoperatively (differs from number identified in pathology).
RESULTS Patient Characteristics Fifty (50) patients were enrolled and completed the study. The distribution of the primary tumor within the breast was upper outer quadrant in 24 patients (48%), upper inner quadrant in 9 patients (18%), lower outer quadrant in 7 (14%), subareolar in 6 (12%), and lower inner quadrant in 4 patients (8%). Mean tumor size was 1.6 cm (range 0.5 to 3.5). Fifty-six percent of patients (28) had nonpalpable tumors at the time of presentation. Five patients had fine needle aspirates (10%), 15 had core needle biopsies (30%), and the remainders had excisional biopsies (60%) to make the initial diagnosis of breast cancer. Injection techniques included four-quadrant injections in 41 patients (82%) and needle localization single dose injections in the others. The majority of patients (80%) underwent breast conservation surgery with the remainder undergoing modified radical mastectomy. Intraoperative Lymphatic Mapping Successful intraoperative lymphatic mapping, defined as the identification of a hot and/or blue node, was achieved in 45 of 50 patients (90%). The average number of sentinel nodes per patient was 1.7 (range 0 to 5). The majority of sentinel nodes harvested were blue and radioactive as can be seen in Table I. Subsequent level I/II axillary node dissection yielded an average of 28.5 nodes per patient (including sentinel nodes). Of the 45 patients in whom a sentinel node was identified, 14 (31.1%) had nodal metastases within their axillary lymphatic basin. All 14 patients had at least one histologically positive sentinel node (0% false negative rate). In 8 of these 14 patients (57%), the sentinel node was the sole site of metastases within the axilla. Lymphoscintigraphy Preoperative lymphoscintigraphy was performed on the first 24 consecutive patients. The patients undergoing lymphoscintigraphy versus those not imaged were comparable with respect to tumor size, biopsy type, the number of resected nodes, and the percent of node-positive patients (Table II). Lymphoscintigraphy performed 30 minutes and 2 hours following radiolabeled colloid injection revealed sentinel nodes in 17 of the 24 patients (70.8%; Figure 1, Table III). Radioactive tracer was seen in axillary node(s) in 16 of 17 patients, with 1 patient having a supraclavicular node. All 17 of the lymphoscintigraphy-positive patients had one or more sentinel nodes identified using intraoperative lymphatic mapping. In addition, 5 of the 7 patients with a
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TABLE II Patient Characteristics Lymphoscintigraphy Group (n ⴝ 24)
No Lymphoscintigraphy (n ⴝ 26)
1.7
1.6
12 (50%) 12 (50%)
18 (69%) 8 (31%)
20 (83%) 4 (17%)
21 (81%) 5 (19%)
19 (79%) 30.6 8
21 (81%) 25.9 6
Mean tumor size (cm) Biopsy type (number of patients) Excisional Incisional (FNA/CNB) Injection technique (number of patients) Four-quadrant Needle localization Breast conservation (number of patients) Total axillary nodes/patient (mean) Number of patients with positive nodes
P Value 0.70 0.25
0.55
0.58 0.39 0.31
FNA ⫽ fine needle aspiration; CNB ⫽ core needle biopsy.
TABLE III Results of Lymphoscintigraphy (n ⴝ 24) Patients with localization by lymphoscintigraphy Node location (17 patients) Axilla Supraclavicular Interval mammary
17 of 24 (71%) 16 1 0
TABLE IV Results of Lymphoscintigraphy (n ⴝ 24)
Figure. Typical lymphoscintigraphy (lateral view) findings in a patient with a primary breast tumor in the upper outer quadrant. Note the axillary sentinel node depicted by the open arrow. The solid arrow depicts the injection site.
negative preoperative lymphoscintigraphy study had a sentinel lymph node identified intraoperatively by the handheld gamma probe (Table IV). In the remaining 2 patients, a sentinel node was not identified during surgery. None of the tumors showed drainage to the internal mammary lymph node chain by lymphoscintigraphy despite the fact that there were 5 patients with inner quadrant tumors. The patient with the supraclavicular node had an upper inner quadrant tumor; a hot Rotter’s node was identified with the gamma detector probe that was histologically negative (as were the remaining nodes). The supraclavicular node could not be identified with the hand-held gamma detector probe and was not biopsied. In retrospect, the radiolabeled colloid may have been injected too deeply into the pectoralis major fascia, resulting in this unusual drainage pattern. Comparison of the preoperative lymphoscintigraphy group with the remainder of the study group (Table V), showed no difference in the percent of successful intraoperative lymphatic mapping procedures (91.7% versus
Patients with no localization by lymphoscintigraphy Primary tumor site (7 patients) Upper outer quadrant Lower outer quadrant Subareolar Sentinel node findings (7 patients) Blue only Hot only Blue and hot No localization
7 of 24 (29%) 5 1 1 0 0 5 2
88.5%; P ⫽ not significant [NS]) or false negative rate (0%, both groups, P ⫽ NS).
COMMENTS The technique of intraoperative lymphatic mapping and sentinel lymph node biopsy is undergoing intense clinical evaluation in patients with invasive breast cancer. It has the potential advantage of being minimally invasive, resulting in less morbidity and reduced cost in node-negative patients. The utilization of this new technology will be driven by both patients and clinicians involved in breast care. To assure reproducible and accurate results, a standardized methodology must be employed. Original studies described the use of blue dye alone,2,4 while others advocated radiolabeled colloid1,5,6,9; more recently there has been a trend toward combining these agents to increase the
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TABLE V Results of Intraoperative Mapping
Percent successful lymphatic mapping (patients) Sentinel nodes/patient (mean) False negative sentinel nodes (patients)
Lymphoscintigraphy Group (n ⴝ 24)
No Lymphoscintigraphy (n ⴝ 26)
P Value
22 (91.7%) 1.6
23 (88.5%) 1.7
1.00 0.85
localization rates and predictive value of intraoperative mapping.3,10 Veronesi et al5 conducted a large trial that employed technetium-labeled albumin as an agent for preoperative lymphoscintigraphy and intraoperative mapping. Sentinel node identification occurred in 98% of patients and the false negative rate was 2.5%. External images were obtained 24 hours prior to surgery, and this technique was reported to be very sensitive in detecting “hot spots” that indicated the location of the sentinel node found during surgery. This success was also observed in a separate study that analyzed a group of patients undergoing lymphoscintigraphy prior to sentinel node biopsy; 89% of patients were imaged successfully.9 In addition, while 16% of patients had internal mammary nodes visualized, in only 2 of 130 patients was the mammary chain the only lymphatic basin visualized; the remainder of patients also had flow to the axilla. The high lymphoscintigraphy localization rates observed in these trials may be a result of studying the patients with a different imaging agent, namely albumin colloid particles. Unfortunately, this agent has not been vigorously evaluated in the United States. It is also possible that the larger numbers of patients in these studies may have allowed the radiologists to overcome an initial “learning curve”; this should be taken into account when interpreting the results of the present study. The lymphoscintigraphy sentinel node localization rate observed in the present study was approximately 71%. The majority of patients (5 of 7) in whom no node was visualized had primary tumors in the upper outer quadrant, and glow from the injection site may have obscured the node, despite shielding. All but 1 of these 5 patients had a sentinel node identified intraoperatively. It was interesting that no internal mammary drainage was seen, especially in the patients with inner quadrant tumors where it would be expected that approximately 24% to 33% of tumors should drain in this fashion based on previous reports analyzing patterns of internal mammary node involvement in breast cancer patients.11,12 Studies evaluating the lymphatic drainage of the normal breast have shown that although most quadrants of the breast drain to the axilla, internal mammary drainage can be seen in 20% to 86% of patients, particularly with lower inner quadrant injections.13,14 In addition, the multicenter validation study reported by Krag et al6 showed 8% of patients had hot spots identified outside of the axilla using the hand-held gamma detector probe. It has also been documented that the great majority of patients with internal mammary nodal metastases also 448
0
0
—
have axillary metastases, suggesting dual lymphatic drainage routes in most patients with inner quadrant lesions.11 Although the internal mammary chain was transcutaneously probed in the current study, a clear emphasis was placed on identifying axillary nodes, which may account for the lack of internal mammary sentinel nodes observed. Since most patients with internal mammary drainage have “primary” drainage to the axilla, the technique employed may have not allowed adequate visualization/localization of secondary drainage basins, such as internal mammary nodes. The present study involved 5 individual surgeons at a single institution, all with varying degrees of experience. No large differences in localization rates were seen among the surgeons (although there was some variation); this supports the observation that the steep learning curves seen in the early studies of lymphatic mapping do not necessarily continue now that the techniques have been refined by the pioneers of the technology. It is important to realize, nevertheless, that any new technique should be adopted only after adequate training and after each surgeon has determined his/her own learning curve. This can only be accomplished by initially following each sentinel node procedure with a standard axillary node dissection and analyzing one’s accuracy. The sentinel node localization rate in this study appears to be consistent with that seen by other authors. In most series, approximately 10% of mapping procedures are unsuccessful. To date it has been difficult to predict which cases will be successful; we currently avoid performing this procedure in patients with very large biopsy cavities, significant hematoma following biopsy, and in patients who have been treated with neoadjuvant chemotherapy. In our current experience with more than 250 patients, we have not observed a significant difference in localization rates in patients undergoing a single image-guided injection when compared with those patients injected using a four-quadrant (multiple site) injection. Increasing the localization rate above 90% would be desirable; currently efforts are under way to achieve this goal. The absence of false negative sentinel nodes observed in this study may be a result of the utilization of both radiolabeled colloid and blue dye, which may increase the sensitivity of detection. Although more than one node was removed from many of these patients, added morbidity was not observed. Certainly the minimal time required for this additional amount of dissection far outweighs the risk of morbidity seen following standard lymphadenectomy. In addition, the added accu-
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racy may result in fewer patients being understaged and thus potentially undertreated with adjuvant therapy. Given the lack of valuable information obtained with routine preoperative lymphoscintigraphy, along with its added time and cost, this procedure is not performed routinely at our center. In theory, it may still be valuable for patients with medial breast tumors with negative axillary nodes if determination of internal mammary nodal involvement would alter adjuvant therapy. Fortunately, this represents only a small number of patients as the majority are receiving adjuvant therapy based upon tumor size, even if node negative. Intraoperative lymphatic mapping with sentinel lymph node biopsy appears to be an accurate method of staging the axilla in clinically node negative breast cancer patients. It is likely to soon replace axillary dissection in most women with breast cancer, once validated in randomized clinical trials. As this technique becomes standard practice, it will be extremely important to prospectively observe these patients for regional recurrences as a method of quality assurance. Furthermore, since the number of positive axillary nodes is important in determining ultimate outcome and in determining the intensity of adjuvant chemotherapy, a patient found to be sentinel node positive should still undergo a standard axillary lymphadenectomy to ensure adequate local control and more accurate staging. This is supported by the observation that approximately 50% of patients with sentinel node metastases will have additional positive nodes found with complete node dissection.5
CONCLUSIONS Sentinel lymph node biopsy is a minimally invasive alternative to axillary node dissection in patients with breast cancer. In this study, preoperative lymphoscintigraphy provided little additional information, and its routine use does not appear justified. Further evaluation in patients with medial quadrant lesions may be warranted.
REFERENCES 1. Krag DN, Weaver D, Alex JC, Fairbank JT. Surgical resection and radiolocalization of the sentinel lymph node in breast cancer using a gamma probe. Surg Oncol. 1993;2:335–339. 2. Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer. Ann Surg. 1994;220:391– 401. 3. Albertini JJ, Lyman GH, Cox C, et al. Lymphatic mapping and sentinel node biopsy in the patient with breast cancer. JAMA. 1196;276:1818 –1822. 4. Giuliano AE, Jones RC, Brennan M, Statman R. Sentinel lymphadenectomy in breast cancer. J Clin Oncol. 1997;15:2345– 2350. 5. Veronesi U, Paganelli G, Galimberti V, et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph nodes. Lancet. 1997;349:1864 –1867. 6. Krag D, Weaver D, Ashkaga T, et al. The sentinel node in breast cancer. A multicenter validation study. NEJM. 1998;33:941–946. 7. Albertini JJ, Cruse CW, Rapaport D, et al. Intraoperative radiolymphoscintigraphy improves sentinel lymph node identification for patients with melanoma. Ann Surg. 1996;223:217–224. 8. McMasters K, Guiliano A, Ross M, et al. Sentinel-lymph-node biopsy for breast cancer-not yet the standard of care. NEJM. 1998; 339:990 –995. 9. Borgstein PJ, Pijpers R, Comans EF, et al. Sentinel lymph node biopsy in breast cancer; guidelines and pitfalls of lymphoscintigraphy and gamma probe detection. J Am Coll Surg. 1998;186:275– 283. 10. Cox CE, Pendas S, Cox JM, et al. Guideline for sentinel node biopsy and lymphatic mapping of patients with breast cancer. Ann Surg. 1998;227:645– 653. 11. Handley R. Carcinoma of the breast. Ann R Coll Surg Engl. 1975;57:59 – 66. 12. LaCour J, Le M, Cacares E, et al. Radical mastectomy versus radical mastectomy plus internal mammary dissection. Cancer. 1983;51:1941–1943. 13. Uren RF, Howman-Giles RB, Thompson JF, et al. Mammary lymphoscintigraphy in breast cancer. J Nucl Med. 1995;36:1775– 1779. 14. Vendrell-Torne E, Setoain-Quinquer J, Domenech-Torne FM. Study of normal lymphatic drainage using radioactive isotopes. J Nucl Med. 1972;13:801– 805.
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Routine Preoperative Lymphoscintigraphy Is Not Necessary Prior to Sentinel Node Biopsy for Breast Cancer William E. Burak, Jr., MD, Michael J. Walker, MD, Lisa D. Yee, MD, Julian A. Kim, MD, Sanjoy Saha, MD, George Hinkle, RPh, John O. Olsen, MD, Rodney Pozderac, MD, William B. Farrar, MD, Columbus, Ohio
BACKGROUND: This prospective study was performed to ascertain the added benefit of lymphoscintigraphy to a standard method of intraoperative lymphatic mapping and sentinel node biopsy for breast cancer. METHODS: Patients with invasive breast cancer were injected with 99mTc sulfur colloid prior to sentinel node biopsy; preoperative lymphoscintigraphy was then performed in half of the patient population. RESULTS: Sentinel node identification was possible in 45 of 50 patients (90%). All 14 patients (31%) with axillary nodal metastases had at least one histologically positive sentinel node (0% false negative rate). Lymphoscintigraphy revealed sentinel nodes in 17 of the 24 patients (70.8%) imaged. All 17 of these patients had one or more axillary sentinel nodes identified using intraoperative lymphatic mapping. In addition, 5 of 7 patients with a negative preoperative lymphoscintogram had an axillary sentinel lymph node(s) identified intraoperatively. None of the tumors showed drainage to the internal mammary lymph node chain by lymphoscintigraphy despite the fact that there were 5 patients with inner quadrant tumors. There was no significant advantage with respect to sentinel lymph node localization (91.7% versus 88.5%, P ⴝ not significant) or false negative rate (0%, both groups, P ⴝ not significant) in the group undergoing preoperative lymphoscintigraphy when compared with the patients in whom lymphoscintigraphy was not performed. CONCLUSIONS: Preoperative lymphoscintigraphy adds little additional information to intraoperative lymphatic mapping, and its routine use is not
From the Division of Surgical Oncology, (WEB, MJW, LDY, JAK, SS, WBF), Department of Surgery, and the Division of Nuclear Medicine, (GH, JOO, RP), Department of Radiology, Arthur G. James Cancer Hospital and Research Institute, Ohio State University Comprehensive Cancer Center, Columbus, Ohio. Requests for reprints should be addressed to William E. Burak, Jr., MD, N914 Doan Hall, 410 W. 10th Avenue, Columbus, Ohio 43210. Manuscript submitted October 16, 1998, and accepted in revised form March 8, 1999.
© 1999 by Excerpta Medica, Inc. All rights reserved.
justified. Am J Surg. 1999;177:445– 449. © 1999 by Excerpta Medica, Inc.
I
ntraoperative lymphatic mapping and sentinel lymph node biopsy is currently undergoing evaluation as an alternative to axillary lymphadenectomy in the clinically node-negative breast cancer patient. Several reports have described the initial success of this minimally invasive alternative to routine lymph node dissection in selected patients.1– 6 Localization of a sentinel node has been shown to be feasible in more than 90% of patients, with falsenegative rates generally less than 10% in larger series of patients. The various techniques utilized involve the use of blue dye and/or radiolabeled colloid as lymphatic mapping agents. Preoperative lymphoscintigraphy is very useful in determining draining nodal basins prior to sentinel node biopsy in patients with melanoma because multiple basins will sometimes drain the same lesion and in transit nodes or unusual locations of sentinel nodes can be recognized prior to surgery.7 Unlike melanoma, breast cancer lymphatic drainage patterns are fairly predictable, with the vast majority of lesions exhibiting primary drainage to axillary lymph nodes. Nevertheless, nonaxillary sentinel nodes have been demonstrated in up to 10% of patients using an intraoperative gamma detector probe.6 To date, the role of preoperative lymphoscintigraphy in breast cancer patients has not been determined,8 although it has been utilized in several major studies as an aid in sentinel node identification.5,9 This prospective study aimed to ascertain the impact of preoperative lymphoscintigraphy on the success and accuracy of intraoperative lymphatic mapping and sentinel lymph node biopsy in patients with breast cancer.
METHODS Patient Selection Fifty patients were enrolled in this nonrandomized prospective study after signing informed consent approved by the Ohio State University Human Subjects Committee. Patients who had a histologic or cytologic diagnosis of breast carcinoma and were to undergo axillary dissection were considered for enrollment if they had unifocal disease, were nonpregnant, and had no palpable axillary adenopathy. Patients with a history of inflammatory breast carcinoma or neoadjuvant therapy were considered ineligible. The first 24 patients underwent preoperative lymphoscintigraphy followed by sentinel node biopsy, while the remaining 26 patients underwent sentinel node biopsy without a preoperative lymphoscintigraphy study. 0002-9610/99/$–see front matter PII S0002-9610(99)00088-4
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Preoperative Lymphoscintigraphy Filtered (0.22 micron) technetium-99m sulfur colloid was injected into the breast parenchyma in a four-quadrant technique around the palpable tumor or biopsy cavity. Each of the four injections was composed of 1 mL saline containing 100 Ci of radiolabeled colloid. For patients who had undergone either a stereotactic or ultrasoundguided core needle biopsy, a single injection of 400 Ci of radiolabeled colloid in 4 mL saline was administered under mammographic or ultrasound guidance at the same time as the needle-wire localization procedure. Preoperative lymphoscintigraphy was performed 30 minutes and at least 2 hours following injection using biplanar imaging. During the first 30 minutes, a 20-minute cine of the chest (anterior projection) was obtained followed by intermittent static images. The framing rate for the cine was 30 seconds per frame, and scintillation camera parameters were 20% window about the 140 keV photopeak. Static images were for 5 minutes’ duration each. The injection site was shielded with lead to enhance visualization of an axillary or mediastinal node. With visualization of the sentinel node(s), additional images in varying degrees of obliquity were performed for more accurate localization of the node(s). When the node was localized, the overlying skin was marked with indelible ink to help facilitate intraoperative node detection. Patients were then transferred immediately to surgery. Intraoperative Lymphatic Mapping Intraoperative lymphatic mapping (ILM) was performed using a combination of blue dye and a hand-held gamma detector probe (Neoprobe Corporation, Dublin, Ohio) to identify radioactivity from lymph nodes containing radiolabeled colloid. Approximately 4 to 5 mL of isosulfan blue dye (Lymphazurin 1%; Ben Venue Laboratories, Bedford, Ohio) was injected into the breast parenchyma in the same fashion as the radiolabeled colloid using either a fourquadrant technique (1 mL per injection) or through the previously placed localization needle. Routine transcutaneous probing of the axillary, internal mammary, and supraclavicular basins was performed. The gamma detector probe displayed counts per second in the scanning mode. “Hot spots” were defined as islands of radioactivity where counts decreased when the probe was moved in any direction from this point. Five to ten minutes following blue dye injection, an axillary incision was made, and attempts were made to identify a blue or radioactive node using visual inspection and the hand-held gamma detector probe. Nodes that demonstrated the presence of blue dye (or had a blue afferent lymphatic) and/or had the presence of radioactive counts above the surrounding tissues were removed and sent to pathology separately. The excised node was probed and counts were obtained to compare with counts of excised adjacent fat to assure the node had counts at least twice that of surrounding fat. A level I/II axillary node dissection was then carried out. The axillary contents were then probed to identify any additional radioactive nodes. Lymph nodes were evaluated using standard hematoxylin and eosin staining. Fisher’s exact test and the Mann-Whitney U test were used in the statistical analysis. 446
TABLE I Characteristics of Sentinel Nodes Sentinel Node* Blue only Radioactive only Blue and radioactive Total
Number 5 (7.7%) 19 (29.2%) 41 (63.1%) 65 (100%)
* Nodes identified intraoperatively (differs from number identified in pathology).
RESULTS Patient Characteristics Fifty (50) patients were enrolled and completed the study. The distribution of the primary tumor within the breast was upper outer quadrant in 24 patients (48%), upper inner quadrant in 9 patients (18%), lower outer quadrant in 7 (14%), subareolar in 6 (12%), and lower inner quadrant in 4 patients (8%). Mean tumor size was 1.6 cm (range 0.5 to 3.5). Fifty-six percent of patients (28) had nonpalpable tumors at the time of presentation. Five patients had fine needle aspirates (10%), 15 had core needle biopsies (30%), and the remainders had excisional biopsies (60%) to make the initial diagnosis of breast cancer. Injection techniques included four-quadrant injections in 41 patients (82%) and needle localization single dose injections in the others. The majority of patients (80%) underwent breast conservation surgery with the remainder undergoing modified radical mastectomy. Intraoperative Lymphatic Mapping Successful intraoperative lymphatic mapping, defined as the identification of a hot and/or blue node, was achieved in 45 of 50 patients (90%). The average number of sentinel nodes per patient was 1.7 (range 0 to 5). The majority of sentinel nodes harvested were blue and radioactive as can be seen in Table I. Subsequent level I/II axillary node dissection yielded an average of 28.5 nodes per patient (including sentinel nodes). Of the 45 patients in whom a sentinel node was identified, 14 (31.1%) had nodal metastases within their axillary lymphatic basin. All 14 patients had at least one histologically positive sentinel node (0% false negative rate). In 8 of these 14 patients (57%), the sentinel node was the sole site of metastases within the axilla. Lymphoscintigraphy Preoperative lymphoscintigraphy was performed on the first 24 consecutive patients. The patients undergoing lymphoscintigraphy versus those not imaged were comparable with respect to tumor size, biopsy type, the number of resected nodes, and the percent of node-positive patients (Table II). Lymphoscintigraphy performed 30 minutes and 2 hours following radiolabeled colloid injection revealed sentinel nodes in 17 of the 24 patients (70.8%; Figure 1, Table III). Radioactive tracer was seen in axillary node(s) in 16 of 17 patients, with 1 patient having a supraclavicular node. All 17 of the lymphoscintigraphy-positive patients had one or more sentinel nodes identified using intraoperative lymphatic mapping. In addition, 5 of the 7 patients with a
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TABLE II Patient Characteristics Lymphoscintigraphy Group (n ⴝ 24)
No Lymphoscintigraphy (n ⴝ 26)
1.7
1.6
12 (50%) 12 (50%)
18 (69%) 8 (31%)
20 (83%) 4 (17%)
21 (81%) 5 (19%)
19 (79%) 30.6 8
21 (81%) 25.9 6
Mean tumor size (cm) Biopsy type (number of patients) Excisional Incisional (FNA/CNB) Injection technique (number of patients) Four-quadrant Needle localization Breast conservation (number of patients) Total axillary nodes/patient (mean) Number of patients with positive nodes
P Value 0.70 0.25
0.55
0.58 0.39 0.31
FNA ⫽ fine needle aspiration; CNB ⫽ core needle biopsy.
TABLE III Results of Lymphoscintigraphy (n ⴝ 24) Patients with localization by lymphoscintigraphy Node location (17 patients) Axilla Supraclavicular Interval mammary
17 of 24 (71%) 16 1 0
TABLE IV Results of Lymphoscintigraphy (n ⴝ 24)
Figure. Typical lymphoscintigraphy (lateral view) findings in a patient with a primary breast tumor in the upper outer quadrant. Note the axillary sentinel node depicted by the open arrow. The solid arrow depicts the injection site.
negative preoperative lymphoscintigraphy study had a sentinel lymph node identified intraoperatively by the handheld gamma probe (Table IV). In the remaining 2 patients, a sentinel node was not identified during surgery. None of the tumors showed drainage to the internal mammary lymph node chain by lymphoscintigraphy despite the fact that there were 5 patients with inner quadrant tumors. The patient with the supraclavicular node had an upper inner quadrant tumor; a hot Rotter’s node was identified with the gamma detector probe that was histologically negative (as were the remaining nodes). The supraclavicular node could not be identified with the hand-held gamma detector probe and was not biopsied. In retrospect, the radiolabeled colloid may have been injected too deeply into the pectoralis major fascia, resulting in this unusual drainage pattern. Comparison of the preoperative lymphoscintigraphy group with the remainder of the study group (Table V), showed no difference in the percent of successful intraoperative lymphatic mapping procedures (91.7% versus
Patients with no localization by lymphoscintigraphy Primary tumor site (7 patients) Upper outer quadrant Lower outer quadrant Subareolar Sentinel node findings (7 patients) Blue only Hot only Blue and hot No localization
7 of 24 (29%) 5 1 1 0 0 5 2
88.5%; P ⫽ not significant [NS]) or false negative rate (0%, both groups, P ⫽ NS).
COMMENTS The technique of intraoperative lymphatic mapping and sentinel lymph node biopsy is undergoing intense clinical evaluation in patients with invasive breast cancer. It has the potential advantage of being minimally invasive, resulting in less morbidity and reduced cost in node-negative patients. The utilization of this new technology will be driven by both patients and clinicians involved in breast care. To assure reproducible and accurate results, a standardized methodology must be employed. Original studies described the use of blue dye alone,2,4 while others advocated radiolabeled colloid1,5,6,9; more recently there has been a trend toward combining these agents to increase the
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TABLE V Results of Intraoperative Mapping
Percent successful lymphatic mapping (patients) Sentinel nodes/patient (mean) False negative sentinel nodes (patients)
Lymphoscintigraphy Group (n ⴝ 24)
No Lymphoscintigraphy (n ⴝ 26)
P Value
22 (91.7%) 1.6
23 (88.5%) 1.7
1.00 0.85
localization rates and predictive value of intraoperative mapping.3,10 Veronesi et al5 conducted a large trial that employed technetium-labeled albumin as an agent for preoperative lymphoscintigraphy and intraoperative mapping. Sentinel node identification occurred in 98% of patients and the false negative rate was 2.5%. External images were obtained 24 hours prior to surgery, and this technique was reported to be very sensitive in detecting “hot spots” that indicated the location of the sentinel node found during surgery. This success was also observed in a separate study that analyzed a group of patients undergoing lymphoscintigraphy prior to sentinel node biopsy; 89% of patients were imaged successfully.9 In addition, while 16% of patients had internal mammary nodes visualized, in only 2 of 130 patients was the mammary chain the only lymphatic basin visualized; the remainder of patients also had flow to the axilla. The high lymphoscintigraphy localization rates observed in these trials may be a result of studying the patients with a different imaging agent, namely albumin colloid particles. Unfortunately, this agent has not been vigorously evaluated in the United States. It is also possible that the larger numbers of patients in these studies may have allowed the radiologists to overcome an initial “learning curve”; this should be taken into account when interpreting the results of the present study. The lymphoscintigraphy sentinel node localization rate observed in the present study was approximately 71%. The majority of patients (5 of 7) in whom no node was visualized had primary tumors in the upper outer quadrant, and glow from the injection site may have obscured the node, despite shielding. All but 1 of these 5 patients had a sentinel node identified intraoperatively. It was interesting that no internal mammary drainage was seen, especially in the patients with inner quadrant tumors where it would be expected that approximately 24% to 33% of tumors should drain in this fashion based on previous reports analyzing patterns of internal mammary node involvement in breast cancer patients.11,12 Studies evaluating the lymphatic drainage of the normal breast have shown that although most quadrants of the breast drain to the axilla, internal mammary drainage can be seen in 20% to 86% of patients, particularly with lower inner quadrant injections.13,14 In addition, the multicenter validation study reported by Krag et al6 showed 8% of patients had hot spots identified outside of the axilla using the hand-held gamma detector probe. It has also been documented that the great majority of patients with internal mammary nodal metastases also 448
0
0
—
have axillary metastases, suggesting dual lymphatic drainage routes in most patients with inner quadrant lesions.11 Although the internal mammary chain was transcutaneously probed in the current study, a clear emphasis was placed on identifying axillary nodes, which may account for the lack of internal mammary sentinel nodes observed. Since most patients with internal mammary drainage have “primary” drainage to the axilla, the technique employed may have not allowed adequate visualization/localization of secondary drainage basins, such as internal mammary nodes. The present study involved 5 individual surgeons at a single institution, all with varying degrees of experience. No large differences in localization rates were seen among the surgeons (although there was some variation); this supports the observation that the steep learning curves seen in the early studies of lymphatic mapping do not necessarily continue now that the techniques have been refined by the pioneers of the technology. It is important to realize, nevertheless, that any new technique should be adopted only after adequate training and after each surgeon has determined his/her own learning curve. This can only be accomplished by initially following each sentinel node procedure with a standard axillary node dissection and analyzing one’s accuracy. The sentinel node localization rate in this study appears to be consistent with that seen by other authors. In most series, approximately 10% of mapping procedures are unsuccessful. To date it has been difficult to predict which cases will be successful; we currently avoid performing this procedure in patients with very large biopsy cavities, significant hematoma following biopsy, and in patients who have been treated with neoadjuvant chemotherapy. In our current experience with more than 250 patients, we have not observed a significant difference in localization rates in patients undergoing a single image-guided injection when compared with those patients injected using a four-quadrant (multiple site) injection. Increasing the localization rate above 90% would be desirable; currently efforts are under way to achieve this goal. The absence of false negative sentinel nodes observed in this study may be a result of the utilization of both radiolabeled colloid and blue dye, which may increase the sensitivity of detection. Although more than one node was removed from many of these patients, added morbidity was not observed. Certainly the minimal time required for this additional amount of dissection far outweighs the risk of morbidity seen following standard lymphadenectomy. In addition, the added accu-
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racy may result in fewer patients being understaged and thus potentially undertreated with adjuvant therapy. Given the lack of valuable information obtained with routine preoperative lymphoscintigraphy, along with its added time and cost, this procedure is not performed routinely at our center. In theory, it may still be valuable for patients with medial breast tumors with negative axillary nodes if determination of internal mammary nodal involvement would alter adjuvant therapy. Fortunately, this represents only a small number of patients as the majority are receiving adjuvant therapy based upon tumor size, even if node negative. Intraoperative lymphatic mapping with sentinel lymph node biopsy appears to be an accurate method of staging the axilla in clinically node negative breast cancer patients. It is likely to soon replace axillary dissection in most women with breast cancer, once validated in randomized clinical trials. As this technique becomes standard practice, it will be extremely important to prospectively observe these patients for regional recurrences as a method of quality assurance. Furthermore, since the number of positive axillary nodes is important in determining ultimate outcome and in determining the intensity of adjuvant chemotherapy, a patient found to be sentinel node positive should still undergo a standard axillary lymphadenectomy to ensure adequate local control and more accurate staging. This is supported by the observation that approximately 50% of patients with sentinel node metastases will have additional positive nodes found with complete node dissection.5
CONCLUSIONS Sentinel lymph node biopsy is a minimally invasive alternative to axillary node dissection in patients with breast cancer. In this study, preoperative lymphoscintigraphy provided little additional information, and its routine use does not appear justified. Further evaluation in patients with medial quadrant lesions may be warranted.
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